Patients with organ transplants have an increased risk of cancer, and organ transplant recipients of European descent are at particularly high risk for developing non-melanoma skin cancers. Although there has been much published on clinical aspects of this risk, there have been relatively few studies of the mechanism underlying its increase. We propose herein an extensive, in depth such study using three individual Projects and two Cores. These Projects will investigate three aspects of the problem: 1. We will investigate the role of aberrant TGFI3 signaling in these tumors, the role of anti-rejection drugs in activating this signaling system, and the effects polymorphisms in the genes encoding members of this pathway have on susceptibility to this post-transplant complication. 2. We will compare genetic abnormalities in squamous cell carcinomas in organ transplant recipients with those present in these tumors in normal patients, expecting that such comparison will help elucidate pathways that are crucial to the increased risk in transplant recipients. Furthermore we will use the overlap of abnormalities in multiple tumors from the same patient to help identify genes with alleles that confer susceptibility vs. resistance to tumorigenesis. 3. We will develop a robust mouse model in which anti-rejection drug treatment enhances skin carcinogenesis and will use this model to test the contribution to enhancement by anti-rejection drug impairment of DNA repair and of immune function. These three will be supported by an Administrative Core and by a Tissue Core that will establish a collection of tumors and blood from very large numbers of organ transplant recipients with tumors and from appropriate controls, a collection that will be essential for the prosecution of the Projects and for future studies of this important clinical problem.